General Background of IBD
The digestive tract, also referred to as the alimentary canal (nourishment canal) or the gut, is part of the digestive system, i.e., the system of organs within multicellular animals which takes in food, digests it to extract energy and nutrients, and expels the remaining waste. This process is called digestion. As defined herein, the digestive tract includes those organs through which food or solid excreta pass in the course of the digestive process, but excludes those organs of the digestive system, adjacent to and connecting with the digestive tract, that store and/or secrete substances aiding in digestion, for example liver, gallbladder and pancreas. This definition is broadly consistent with that given in standard reference works such as Dorland's Illustrated Medical Dictionary, 30th ed. (2003), Saunders, Philadelphia, which defines the digestive tract as that part of the digestive system formed by the esophagus, stomach and intestines, except that for convenience herein the mouth and pharynx are also included. In a normal human adult male, the digestive tract from mouth to anus is approximately 7.5 meters long and consists of upper and lower portions with the following components:                upper digestive tract: mouth (oral or buccal cavity; includes salivary glands, oral mucosa, teeth and tongue), pharynx, esophagus (gullet) and cardia, stomach, which includes the antrum and pylorus and the pyloric sphincter;        lower digestive tract: bowel or intestines, consisting of (a) small intestine, which has three parts: duodenum, jejunum and ileum; (b) large intestine, which has three parts: cecum (including the vermiform appendix which is a diverticulum of the cecum), colon (ascending colon, transverse colon, descending colon and sigmoid flexure), and rectum; and (c) anus.        
The term “gastrointestinal tract” or “GI tract” is sometimes used herein, as commonly in the art, to refer to the entire digestive tract. If used in its strict sense, meaning that part of the digestive tract formed by stomach and intestines, such use is expressly specified herein or will be required by the context.
Inflammatory bowel disease (IBD) is a class of idiopathic diseases of the digestive tract that are believed to involve an autoimmune reaction. Two major types of IBD are recognized: ulcerative colitis (UC) and Crohn's disease (CD). UC, also known as idiopathic proctocolitis, is typically limited to the colon; CD, also referred to as regional enteritis, terminal ileitis or granulomatous ileocolitis, can involve any segment or segments of the digestive tract from the mouth to the anus. Where the term “inflammatory bowel disease” or “IBD” is used herein, particularly with reference to CD, it will be understood to include manifestations anywhere in the digestive tract, not exclusively in the bowel.
UC and CD exhibit significant differences, but both diseases share a number of intestinal and extraintestinal manifestations, although some of these tend to occur more commonly in one disease or the other. Both UC and CD usually exhibit waxing and waning intensity and severity. When an IBD patient has symptoms indicating significant inflammation, the disease is considered to be in an active stage; such a patient is said to be having a “flare” of the IBD. When inflammation is of lesser severity or absent and the patient substantially asymptomatic, the disease is considered to be in remission. In most cases, symptoms correspond well with the degree of inflammation present for either disease, although this is not universally true. In some patients, objective evidence for disease activity may be needed before administering medications with potential for significant adverse side effects.
Information on IBD, its symptoms, pathology and treatment can be found in various print and internet sources, including for example those individually cited below and incorporated herein by reference.
Bonner (2003) “Inflammatory bowel disease: advances in medical management.” http://www.fascrs.org/displaycommon.cfm?an=1&subarticlenbr=113.
Tung & Warner (2002) Postgraduate Medicine 112(5). “Colonic inflammatory bowel disease: medical therapies for colonic Crohn's disease and ulcerative colitis.” http://www.postgradmed.com/issues/2002/11—02/tung2.htm.
University of Maryland Medical Center (2002) “What are the Drug Treatments for Inflammatory Bowel Disease?” http://www.umm.edu/patiented/articles/what_drug_treatments_inflammatory_bowel_disease—000069—9.htm.
Ulcerative Colitis: Symptoms and Pathology
Patients with UC most commonly present with bloody diarrhea. Abdominal pain and cramping, fever and weight loss occur in more severe cases. The greater the extent of colon involvement, the more likely the patient is to have diarrhea. Rectal urgency (tenesmus) can be associated with inflamed rectum. Patients might have formed stools if their disease is confined to the rectum. As the degree of inflammation increases, systemic symptoms develop, including low-grade fever, malaise, nausea, vomiting, sweats and arthralgias. Fever, dehydration and abdominal tenderness develop in severe UC, reflecting progressive inflammation into deeper layers of the colon.
Diagnosis of UC can be made endoscopically or radiologically, with contrast radiographs typically showing loss of the normal mucosal pattern and, with more advanced disease, loss of colonic haustrae. Sigmoidoscopy or colonoscopy reveals that the rectum is almost always involved. The disease can be limited to the rectum (proctitis), in about 25% of patients; to the rectum, sigmoid, and descending colon (left-sided colitis), in most patients; or to the entire colon (pancolitis), in about 10% of patients. UC does not involve any other segment of the gastrointestinal tract. Colectomy is curative.
In UC, a clear demarcation exists between involved and uninvolved mucosa; and in the involved area, the disease is strikingly and uniformly continuous. UC primarily involves the mucosa and the submucosa, with formation of crypt abscesses and mucosal ulceration. The mucosa typically appears granular and friable. In more severe cases, pseudopolyps form, consisting of areas of hyperplastic growth with swollen mucosa surrounded by inflamed mucosa with shallow ulcers. In severe UC, inflammation and necrosis can extend below the lamina propria to involve the submucosa and the circular and longitudinal muscles, although this is unusual. As the disease becomes chronic, the colon becomes a rigid foreshortened tube that lacks its usual haustral (out-pouch) markings, leading to the “lead pipe” appearance observed on barium enema.
Regarding prognosis for UC, only a small percentage of patients have a single attack and no recurrence. Typically, however, remissions and exacerbations are characteristic of UC, with acute attacks lasting weeks to months. Twenty percent of patients require colectomy, which is curative. Long-term morbidity primarily results from complications of medical therapy, especially long-term steroids.
The most common causes of death in IBD are peritonitis with sepsis, malignancy, thromboembolic disease, and complications of surgery. Toxic megacolon, one of the most dreaded complications of UC, can lead to perforation, sepsis, and death. Malignancy is the most dreaded long-term intestinal complication of UC, as the risk of colon cancer begins to rise significantly above that of the general population approximately 8-10 years after diagnosis. Colonic strictures in persons with UC are presumed to be malignant unless proven otherwise (usually by resection).
Crohn's Disease: Symptoms and Pathology
The presentation of CD is generally more insidious than that of UC, with ongoing abdominal pain, anorexia, diarrhea, weight loss and fatigue. Grossly bloody stools, while typical of UC, are less common in CD. Stools may be formed, but loose stools predominate if the colon or the terminal ileum is involved extensively. One half of patients with CD present with perianal disease (e.g., fistulas or abscesses). Occasionally, acute right lower quadrant pain and fever may be noted, mimicking appendicitis. Commonly, the diagnosis is established only after several years of recurrent abdominal pain, fever, and diarrhea. CD with gastroduodenal involvement may mimic peptic ulcer disease and can progress to gastric outlet obstruction.
Weight loss is observed more commonly in CD than in UC because of the malabsorption associated with small bowel disease. Patients may reduce their food intake in an effort to control their symptoms. Systemic symptoms are common and include fever, sweats, malaise and arthralgias. A low-grade fever may be the first warning sign of a flare. Recurrences may occur with emotional stress, infections or other acute illnesses, pregnancy, dietary indiscretions, use of cathartics or antibiotics, or withdrawal of anti-inflammatory or steroid medications.
Children may present with growth retardation and delayed or failed sexual maturation. In 10-20% of cases, patients present with extraintestinal manifestations, including arthritis, uveitis or liver disease.
Diagnosis of CD can be made endoscopically or radiologically, with contrast radiographs typically showing a cobblestone pattern to the mucosa, with areas of normal mucosa alternating with areas of inflamed mucosa (“skip lesions”). The most important pathologic feature is involvement of all layers of the bowel, not just the mucosa and the submucosa, as is characteristic of UC. Sigmoidoscopy or colonoscopy reveals that the rectum is frequently spared and right colonic predominance is common. Ninety percent of patients with CD have involvement of the terminal ileum and/or right colon. Pediatric patients are more likely (about 20%) to present with disease limited to the small intestine. Much less commonly, CD involves the more proximal parts of the gastrointestinal tract, including the mouth, tongue, esophagus, stomach and duodenum.
Strictures and obstructions in persons with CD are often inflamed and frequently resolve with medical treatment. Fixed (scarred or cicatrix) strictures may require endoscopic or surgical intervention to relieve obstructions. Fistulae and perianal disease in persons with CD may be refractory to vigorous medical treatment, including antibiotic therapy. Surgical intervention is often required for fistulae and perianal disease treatment, but both are associated with a high risk of recurrence. The risk of cancer in persons with CD may be equal to that of persons with UC if the entire colon is involved, and the risk of small intestine malignancy is increased in persons with CD, but the malignancy is as likely to arise in a previously normal area as in an inflamed area.
Prognosis for CD depends on the site and extent of disease. Periodic remissions and exacerbations are the rule. Approximately 50% of patients require surgical intervention; 50% of patients undergoing surgery require a second operation; of these patients, 50% have a third operation. Rate of recurrence is 25-50% within one year for patients who have responded to medical management. This rate is higher for patients who require surgery.
The quality of life generally is lower with CD than with UC, in part because of recurrences after surgery performed for CD. Malnutrition and chronic anemia are observed in long-standing CD. Children with CD or UC can exhibit growth retardation.
Prevalence and Incidence of IBD
IBD is observed most commonly in Northern Europe and North America. It is a disease of industrialized nations. In the U.S., approximately 1 million people have UC or CD. Before 1960, the reported incidence of UC was several times higher than that of CD. More recent data suggest that the current incidence of CD is approaching that of UC, although this change may reflect improved recognition and diagnosis of CD.
In the U.S., rates of IBD occurrence among persons of European descent have been measured, for instance, in Olmsted County, Minn. It is reported that in this population, the incidence of UC is 7.3 cases per 100,000 people per year and the prevalence is 116 cases per 100,000 people; the incidence of CD is 5.8 cases per 100,000 people per year and the prevalence is 133 cases per 100,000 people. The incidence of IBD has been reported to be highest in Ashkenazi Jews (i.e., those who have immigrated from Northern Europe), at 4-5 times that of the general population, followed by non-Jewish white populations. However, recent data suggest that incidences in non-Jewish, black, and Hispanic populations are increasing. The male-to-female ratio is approximately equal for both UC and CD. A recent study in Italy showed incidences of UC and CD similar to those in the U.S.
UC and CD are most commonly diagnosed in young adults (i.e., late adolescence to the third decade of life). The age distribution of newly diagnosed IBD cases is bell-shaped; the peak incidence occurs in people in the early part of their second decade of life, with the vast majority of new diagnoses made in people aged 15-40 years. A second smaller peak occurs in patients aged 55-65 years. However, children younger than 5 years and elderly persons are occasionally diagnosed. Only about 10% of patients with IBD are younger than 18 years. Incidence may be slightly greater in females than in males.
Medical Treatment of IBD
Care of a patient with IBD can be either medical or surgical in nature, or commonly a combination of both. Medications used for IBD are broken down into several classes based on chemical similarities of the individual agents and similarities in the mechanisms of action. The medical approach for patients with IBD is symptomatic (flaring) care and generally follows a stepwise approach to medication therapy, with progression of the medical regimen until a response is achieved. With this approach, the most benign (or temporary) drugs are used first. As they fail to provide relief, drugs from a higher step are used.
Aminosalicylates and symptomatic agents are step I drugs under this scheme; antibiotics are considered step IA drugs, given the limited situations in which they are used. Corticosteroids constitute step II drugs to be used if the step I drugs fail to adequately control the IBD. Immune modifying agents are step III drugs and are used if corticosteroids fail or are required for prolonged periods. Infliximab, a monoclonal antibody against tumor necrosis factor (TNF) α, is also a step III drug that can be used in some situations in patients with CD and UC. Experimental agents are step IV drugs and are used only after the previous steps fail, and then are administered only by physicians familiar with their use. Drugs from all steps may be used additively; in general, the goal is to wean the patient off steroids as soon as possible to prevent long-term adverse effects from these agents. Opinions differ regarding the use of certain agents in this stepwise approach.
Step I (aminosalicylates). Oral aminosalicylate preparations available for use in the U.S. include sulfasalazine, mesalamine, balsalazide and olsalazine. Enema and suppository formulations are also available. All of these are derivatives of 5-aminosalicylic acid (5-ASA); the major differences are in the mechanism of delivery. Some of these also have unique adverse effects that other agents of this class lack. All of the aminosalicylates are useful for treating flares of IBD and for maintaining remission. None of the aminosalicylates has been proven to have greater efficacy for treatment of UC or CD over any of the others. All of them are clearly more effective in persons with UC than in persons with CD; in CD, the primarily utility is for colonic disease.
Step IA (antibiotics). The antibiotics metronidazole and ciprofloxacin are the most commonly used antibiotics in IBD. Antibiotics are used only sparingly in UC because UC increases the risk of developing antibiotic-associated pseudomembranous colitis. However, in CD, antibiotics are used for a variety of indications, most commonly for perianal disease. They are also used for fistulae and inflammatory masses in the abdomen, and they may have some efficacy in treating ileitis. The antibiotics have potential adverse effects, including nausea, anorexia, diarrhea, monilial (candidal) infections and, in the case of metronidazole, peripheral neuropathy.
Step II (corticosteroids). Corticosteroids are rapid-acting anti-inflammatory agents used in treatment of IBD for acute flares of disease only; corticosteroids have no role in maintenance of remission. Corticosteroids may be administered by a variety of routes depending on the location and severity of disease; for example they may be administered intravenously (e.g., methylprednisolone, hydrocortisone), orally (e.g., prednisone, prednisolone, budesonide, dexamethasone), or topically (enema, suppository or foam preparations).
Intravenous corticosteroids are often used for patients who are severely ill and hospitalized. In general, once a clinical response is observed (typically within 1-2 days, occasionally longer), the dose of the intravenous corticosteroid can be tapered. Before hospital discharge, conversion to an oral corticosteroid is made; further dosage tapering can be accomplished in an outpatient setting. Again, once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can only occasionally tolerate a relatively rapid taper after a response is achieved; occasionally, a very prolonged steroid taper is necessary to prevent relapse. When the latter situation occurs, alternative drugs (immune modifiers or anti-TNFα therapy) may be used. Topical corticosteroids are used in persons with distal colonic disease in a manner similar to topical mesalamine, but typically only for active disease as topical corticosteroids have only a small role in the maintenance of remission.
The potential complications of corticosteroid use are multiple and include fluid and electrolyte abnormalities, osteoporosis, aseptic necrosis, peptic ulcers, cataracts, neurologic and endocrine dysfunctions, infectious complications, and occasional psychiatric disorders (including psychosis).
Step III (immune modifiers). The immune modifiers azathioprine and 6-mercaptopurine (6-MP) are used in patients with IBD in whom remission is difficult to maintain with aminosalicylates alone. Immune modifiers work by causing a reduction in lymphocyte count, and because of that mechanism of action, their onset of action is relatively slow (typically 2-3 months). They are used most commonly for their steroid-sparing action in persons with refractory disease; they are also used as primary treatment for fistulae and the maintenance of remission in patients intolerant of aminosalicylates.
Use of these agents mandates monitoring of blood parameters; they can cause significant neutropenia or pancytopenia that would warrant a dose reduction or discontinuation. Other adverse effects of the immune modifiers include fever, rash, infectious complications, hepatitis, pancreatitis and bone marrow depression. The most common reason for discontinuing immune modifiers within the first few weeks is development of abdominal pain; occasionally, a biochemically demonstrable pancreatitis occurs. Concerns have been raised about development of malignancy in patients taking azathioprine and 6-MP.
Infliximab is an additional step III agent that works by a different mechanism. Infliximab is an anti-TNFα monoclonal antibody that is currently U.S. Federal Drug Administration (FDA) approved for both UC and CD, although it does appear to have a higher efficacy rate in CD. Infliximab is generally administered as infusions of 5 mg/kg for treatment of moderate to severe IBD. It is administered as 3 separate infusions of 5 mg/kg at weeks 0, 2, and 6, often followed by doses every 8 weeks for maintenance of remission. For CD, the response rate is 80% and the induction of remission rate is 50% after a single dose; with multiple dosing, higher rates of remission are attained. For UC, the response rates are 50-70%. Infliximab is also indicated for treatment of fistulizing CD; for this indication, the fistula responds (closes) in 68% of patients treated with infliximab, although 12% develop an abscess. The response can be maintained by continuing regular dosing (i.e., every 8 weeks) after the induction dose.
Infliximab treatment is extremely expensive and may also involve adverse effects, commonly including hypersensitivity and flu-like symptoms. Rare instances of lupus-like reactions and lymphoproliferative malignancies have been reported, although whether the malignancies are related to the drug or to the underlying disease process remains uncertain.
Step IV (experimental treatments). Experimental agents used in CD include methotrexate (12.5-25 mg/week orally or intramuscularly), thalidomide (50-300 mg/day orally), and interleukin 11 (1 mg/week subcutaneously). Experimental agents used in UC include cyclosporin A at a dose of 2-4 mg/kg/day intravenously (measure level; convert to oral dosing at 2-3 times the intravenous dose), nicotine at 14-21 mg/day via topical patch, butyrate enema (100 ml per rectum twice daily), and heparin (10,000 U subcutaneously twice daily). Multiple contraindications, interactions and precautions are associated with these drugs.
Chronic Gastritis
Chronic gastritis, a chronic inflammation of the stomach mucosa, is most often caused by infection with the bacterium Helicobacter pylori, but may also be caused by nonsteroidal anti-inflammatory drug (NSAID) use, autoimmunity, allergy, or other factors. Infectious gastritis is usually treated with multiple drug therapy, comprising an antibiotic to eliminate the underlying infection, and one or more drugs to treat the inflamed mucosa. Current drugs, used either with antibiotics to treat infective gastritis or alone to treat other forms of gastritis, are of two main classes: proton-pump inhibitors and H2-receptor blockers, both of which act by inhibiting gastric acid secretion. However, in many cases these methods are ineffective or not completely effective, and new modalities of treatment are needed.